The overall goal of this A1 resubmission is to advance the understanding of human [unreadable]2-adrenergic receptor ([unreadable]2-AR) gene haplotype variation and cardiovascular phenotype. An emerging but yet to be defined relationship exists in humans between [unreadable]2-AR haplotype, the pressor response to sympathoexcitatory maneuvers like mental stress and handgrip, [unreadable]2-mediated cardiac and vascular function, and dietary sodium manipulation. Single nucleotide polymorphisms (SNP's) encoding the 16th and 27th amino acid in the [unreadable]2- AR gene have been characterized in combination, whereas the need exists to examine the functional relevance of the three, most common haplotypes in an ethnically homogenous cohort, thus controlling for variation in SNP's and race/ethnicity. Our strategy is to perform hypothesis-driven protocols with respect to [unreadable]2-AR haplotype on physiological and pharmacological responses pertinent to the pathogenesis of hypertension and cardiovascular disease in Caucasians. In AIM 1 we test whether individuals homozygous for common haplotypes in the [unreadable]2-AR influence the cardiovascular and regional vasodilator responses to sympathoexcitatory maneuvers following a normal sodium diet. We hypothesize that healthy individuals carrying the haplotype homozygous for glycine at position 16 (Gly16) and glutamate at position 27 (Glu27) (haplotype 1) will demonstrate greater cardiac output and lower systemic vascular resistance during mental stress and isometric handgrip exercise than individuals with haplotypes homozygous for arginine (Arg16) + glutamine (Gln27) (haplotype 2) and Gly16 + Gln27 (haplotype 3). In AIM 2 we test whether common haplotypes in [unreadable]2-AR influence the cardiovascular and regional vasodilator responses to sympathoexcitatory maneuvers after 5 days of dietary sodium restriction, followed by 5 days of dietary sodium loading. We hypothesize the greater cardiac output and systemic [unreadable]2-AR mediated vasodilation in haplotype 1 following normal dietary sodium intake will no longer be seen following dietary sodium restriction, and these responses will be augmented following sodium loading. In AIM 3 we test whether common haplotypes in [unreadable]2- AR influence the cardiovascular and regional vasodilator responses to systemic infusions of [unreadable]2-AR agonist, after temporary pharmacological ablation of baroreflex control of the circulation. We hypothesize a) that after baroreflex ablation, the haplotype 1 will be associated with greater cardiac output and greater systemic [unreadable]2-AR mediated vasodilation than haplotypes 2 and 3 during systemic [unreadable]2-AR agonist infusion;b) that effects of [unreadable]2- AR haplotype variation on systemic vascular resistance will be dependent on [unreadable]2-AR mediated production of nitric oxide. Finally, we hypothesize that ex vivo determination of lymphocyte [unreadable]2-AR's present in the high affinity binding conformation will mechanistically explain the influence of dietary sodium manipulation on haplotype-dependent differences in cardiovascular function. The mechanistic high-resolution phenotyping in this proposal will provide important new genetic insight about the pathogenesis of cardiovascular disorders. PUBLIC HEALTH RELEVANCE The overall goal of this project is to advance the understanding of how genetic variation in a major heart and blood vessel receptor (the beta-2 adrenergic receptor) influences cardiovascular regulation. Healthy young adult volunteers will be grouped according to diverse yet commonly inherited forms of the beta-2 receptor. By determining the genetic influence of blood pressure regulation in response to stressful maneuvers, medication infusions, and dietary sodium intake, this strategy will provide mechanistic detail of how genes interact with intermediate physiological traits pertinent to the development of hypertension and cardiovascular disease.